The present invention relates to the preparation of pharmaceutical active ingredients, and in particular to the preparation of medicaments active in the treatment of Parkinson""s disease.
Alkaloids having an ergoline structure exhibit a wide spectrum of biological effects which include both peripheral effects (vasoconstrictor and contractile effect on the smooth muscle of the uterus) and effects on the central nervous system (various sites of action are located in vasomotor centres and cardiac inhibitor centres found in the medulla oblongata and in sympathetic structures found in the diencephalon).
Some of those alkaloids, such as ergotamnine, ergometrinc, ergosine, crgocrystine and ergocryptine, are entirely of natural origin because they can be isolated from the fungus Claviceps purpurea. That fungus is a member of the class of Ascomycetes which is capable of infesting many cereals, such as rye, barley and wheat; its sclerotium contains a high percentage (0.5-0.8% by weight) of alkaloids having an ergoline structure which are responsible for its known toxic properties. Other compounds are of a semi-synthetic nature and are prepared by chemical modification of naturally occurring alkaloids having an ergoline structure. Noteworthy among the above-mentioned semi-synthetic derivatives are bromocryptine, [CAS 25614-03-3], lysuride [CAS 18016-80-3) and pergolide (FIG. 1), namely (8)-8-[(methylthio)methyl]-6-propylergoline [CAS 66104-22-1]; this last-mentioned compound in particular is a semi-synthetic ergoline used in therapy for the treatment of Parkinson""s disease 
The processes for the synthesis and purification of that molecule are described in U.S. Pat. No. 4,166,182 and U.S. Pat. No. 5,463,060; those patents, however, describe synthetic approaches which, according to the authors themselves, are not entirely satisfactory from several points of view. The impurities which arise during the synthesis processes described in U.S. Pat. No. 4,166,182 and U.S. Pat. No. 5,463,060 are difficult to remove without significant losses in yield (J. Kennedy et al., Org. Process Res. Dev. (1997), 1(1), 68-71); furthermore, the process described in U.S. Pat. No. 4,166,182, has low yields and requires long operating times (J. W. Misner et al., Book of Abstracts, 210th ACS National Meeting, Chicago, Ill., Aug. 20-24 (995). Publisher: American Chemical Society, Washington, D.C.).
To be more precise, U.S. Pat. No. 4,166,182 describes the synthesis of pergolide mesylate with 22% yields starting from D-8-methoxycarbonylergoline. The synthesis and chromatographic purification steps make the process particularly complicated; the basic pergolide, obtained with a 38% yield starting from D-8-methoxycarbonylergoline, also requires a further purification step by salification using methanesulphonic acid.
U.S. Pat. No. 5,463,060, on the other hand, describes the synthesis of the basic pergolide starting from 8,9-dihydroelymoclavine with 90.8% yields and with a titre of 94.1%. 8,9-dihydroelymoclavine (CAS 18051-16-6) is, however, a semi-synthetic alkaloid derivative which is not readily available because it is obtained from lysergic acid by means of numerous synthesis steps (see, for example: HU 89-3223 890627; R. Voigt et al. Phanirazie (1973), 2; S. Miroslav et al. Collect.Czech.Chem.Commun. (1968), 33(2), 577-82); the synthetic steps necessary to carry out the above-mentioned conversion arc also especially onerous because they require, inter alia, stereoselective hydrogenation of the double bond in the 9,10 position and the reduction of the 8 carboxylic function to an alcoholic function (upon conversion into methyl ester).
The object of the present invention is therefore to provide an alternative process for the production of pergolide which permits yields and purities higher than those of U.S. Pat. No. 4,166,182 and which uses a starting compound which is more readily available than 8,9-dihydroelymoclavine.
Medicaments active in the treatment of Parkinson""s disease which can be prepared in accordance with the process of the present invention comprise products which have the following general formula VI: 
wherein R4 may be, independently, a linear, branched or cyclic, saturated or unsaturated C1-8 alkyl radical, such as, for example, the radicals methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl and octyl; the preferred compound includes, but is not limited only to, the pergolide (R4=CH3).
The process for the synthesis of those compounds, which forms the main subject of the present invention, uses as starting material the compound of formula I given below, wherein R1 represents a linear, branched or cyclic, saturated or unsaturated C1-8 akyl residue, preferably methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl and octyl, and even more preferably methyl, or the well known and readily available D-8-methoxycarbonylergoline [CAS 30341-92-5]. 
In that process, the compounds of formula I are reacted with 3-halo- and/or 2-halo-propionyl chloride in an aprotic organic solvent in the presence of a suitable proton acceptor. Solvents that may be used in that step are preferably selected from acetone, methyl ethyl ketone, tetrahydrofuran and dimethylformamide; the proton acceptor is preferably selected from triethylaniine, pyridine and lutidine. Both the proton acceptor and the 3-halo- and/or 2-halo-propionyl chloride are preferably used in equimolar amounts relative to the compound of formula I.
The compound or mixture of compounds IIa and IIb so obtained is then reacted with calcium borohydride in an amount of preferably from 5 to 9 moles/mole of substrate in tetrahydrofuran. The tetrahydrofuran is preferably present in an amount of from 2 to 8 ml per gram of substrate; optionally, it may be used in admixture with protic organic solvents, such as methanol, ethanol or isopropanol, or with an aqueous-alcoholic solution thereof. The reaction is carried out at a temperature of from 10 to 65xc2x0 C., preferably at 60xc2x0 C.
Compound III so obtained is then reacted in an aprotic organic solvent with an alkylsulphonyl chloride in the presence of a proton acceptor at a temperature of preferably from 10 to 30xc2x0 C.; the proton acceptors are preferably selected from pyridine, triethylaniine, lutidine; the alkylsulphonyl chlorides are preferably selected from methanesulphonyl chloride, ethanesulphonyl chloride and p-toluenesulphonyl chloride. The proton acceptor and the alkylsulphonyl chloride are preferably used in amounts of from 20 to 30 and from 1.2 to 3 moles/mole of substrate, respectively.
Compound IV so obtained is then reacted in an aprotic organic solvent with a compound of the general formula R4SX, wherein R4 is a linear, branched or cyclic, saturated or unsaturated C1-8 alkyl residue, preferably methyl, and X is an alkali metal, preferably sodium. The compound R4SX is preferably used in an amount equal to 4-8 equivalents relative to the substrate; the apolar organic solvent is preferably dimethylformamide; the reaction is preferably carried out at a temperature of from 90 to 100xc2x0 C.
Finally, compound V so obtained is converted into the desired end product by treatment with a reducing agent in an aprotic organic solvent at a temperature of preferably from 20 to 45xc2x0 C. Reducing agents that may be used in that step are preferably selected from lithium aluminium hydride and sodium dihydro-bis(2-methoxyethoxy)aluminate; aprotic solvents that may be used in that step are preferably selected from tetrahydrofuran, dioxane and toluene.
For greater clarity, the novel process according to the present invention is shown in the following reaction schemes 1, 2 and 3. 
wherein R1 represents a linear, branched or cyclic, saturated or unsaturated C1-8 alkyl residue, such as, for example, the radicals methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl and octyl, preferably a methyl group; R2 is a halogen (Cl, I, Br), preferably chlorine (Cl), X is an iodine molecule or a compound of the general formula R5SO3 wherein R5 is methyl, ethyl or p-tolyl, preferably methyl; R4 is, independently, a linear, branched or cyclic, saturated or unsaturated C1-8 alkyl residue, such as, for example, the radicals methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, preferably a methyl group. 
wherein R1, R2, R4 and X have been defined above. 
wherein R1, R4 and X have been defined above.
The novel intermediates of formula II, III, IV and V, which are given individually below for greater clarity, constitute a further subject of the invention. 
wherein R1 and R3 may be a halogen (Cl, I, Br) and hydrogen (H), respectively; alternatively, R2 and R3 may be bonded to one another directly giving rise to a double bond; and R1 represents a linear, branched or cyclic, saturated or unsaturated C1-8 alkyl residue, such as, for example, the radicals methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl and octyl; the preferred molecules are represented by the compounds IIa (R3=H; R2=Cl; R1=CH3) and IIb (R3 and R2 joined together to give rise to a double bond; R1=CH3). 
wherein X is a halogen (X=I, compound IVb) or a compound of the general formula R5SO3xe2x80x94 wherein R1 is methyl, ethyl or p-tolyl; the preferred molecule is represented by the compound IVa(X=CH3SO3xe2x80x94). 
wherein R4 is, independently, a linear, branched or cyclic, saturated or unsaturated C1-8 alkyl residue, such as, for example, the radicals methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl; the preferred molecule is represented by the compound Va (R2=CH3).
In order to obtain quantitative conversion of the 8-methoxycarbonylergoline into the intermediate III, a series of acylating agents, such as 3-halo- and 2-halo-propionyl chlorides, were evaluated. The halogen derivatives tested were chlorine, iodine and bromine derivatives.
As is well known to experts in the field, the presence of an electron-attracting group (such as a chlorine, bromine or iodine atom) in the alpha or beta position to an acid chloride increases the latter""s reactivity in acylation reactions.
During the research work which led to the present invention, it was hoped to find, by screening reducing agents, a reagent which exhibited a high degree of chemoselectivity towards the intermediate chlorine derivative of formula II (R2=alogen, R2=H or R2=H, R2=halogen). The reducing agent was intended to replace the halogen in the alpha (or beta) position to the acylamide function with a hydrogen atom and reduce the methoxycarbonyl function in the 8 position to an alcoholic function without reducing the amide group in position 6.
We ascertained experimentally that by using an equimolar amount of 3-chloropropionyl chloride in the presence of a proton acceptor in acetone solution under stirring at room temperature, D-8-methoxycarbonylergoline gave, in addition to the desired product (D-6-(3xe2x80x2-chloropropionyl)-8-methoxycarbonylergoline; compound IIa), a side product which was subsequently identified as D-6-(acryloyl)-8-methoxycarbonylergoline (compound IIb). The presence of this side product IIb was initially regarded as a critical factor for the industrial development of the process because, even if the presence of compound IIb could be contained by suitably varying the experimental conditions (slow addition of the acylating agent, low reaction temperatures, low concentrations of the reagents) nothing was known of the possible influence of that secondary product on the subsequent synthetic steps.
Surprisingly, the screening carried out on a number of reducing agents under various experimental conditions on a mixture constituted to the extent of 50% by compound IIb and compound IIa demonstrated not only that calcium borobydride in tetrahydrofuran was capable of showing the desired chemoselectivity (removal of the chlorine in position 3xe2x80x2 and reduction of the 8-methoxycarbonyl group without reducing the amide in position 6) but also that compound IIb was converted into the desired compound of formula III.
The surprising reactivity of the double bond of compound rib with calcium borohydride in tetrahydrofuran gave us the possibility, which was not foreseeable from the literature, of using the reaction mixture obtained directly from the acylation reaction of D-8-methoxycarbonylergoline without purification in the subsequent reaction step.
Thus, by reacting a mixture of D-8-methoxycarbonylergoline in an aprotic solvent, in concentrations ranging from 8 to 18% weight/volume, under stirring at room temperature, with an equimolar amount of a suitable proton acceptor and one equivalent of 3-halo- or 2-halo-propionyl chloride for a period ranging from 30 minutes to 2 hours, we obtained, after dilution with water and filtration, a mixture of which approximately 50% was constituted by compound IIa and compound IIb.
Aprotic solvents that may be used in that step are represented by acetone, methyl ethyl ketone, tetrahydrofuran, dimethylformamide, preferably acetone; proton acceptors that may be used are triethylamine, pyridine and lutidine, preferably triethylamine.
The mixture of compound IIa and compound IIb is dispersed in tetrahydrofuran with sodium borohydride (from 5 to 9 moles per mole of substrate) and the suspension so obtained is added, at a temperature ranging from 0 to +15xc2x0 C. and under vigorous stirring, to a tetrahydrofaran solution or to an alcoholic solution (methanol, ethanol or isopropanol) or an aqueous-alcoholic solution containing calcium chloride (from 1.5 to 2 moles per mole of sodium borohydride). When the addition is complete, the temperature is increased to 60xc2x0 C. and the reaction mixture is maintained under stirring for a period ranging from 20 minutes to 60 minutes. The compound III so obtained is precipitated from the reaction mixture (after acidification of the reaction mixture, evaporation of the organic phase and treatment with aqueous carbonate) and recovered by filtration.
Alternatively, the calcium borohydride, instead of being produced xe2x80x9cin situxe2x80x9d, can be used already preformed in the commercially available forms (for example, as a bis-THF complex).
On the basis of the data obtained, compound III can be prepared in accordance with Scheme 1 with total yields of 81% starting from D-8-methoxycarbonylergoline.
It was clear from the results obtained that, in order to synthesise the compound of formula III, it would have been equally advantageous to acylate compound I directly with acryloyl chloride (Scheme 3) or to use the intermediate IIa with a high degree of chemical purity (obtainable by the acylation of compound I with chloropropionyl chloride carried out at low temperatures (0-5xc2x0 C.) and high dilutions (0.05-0.2 molar); Scheme 2) and to reduce the intermediate IIb or IIa so obtained with calcium borohydride in the next step. An experimental check carried out on those two variants confirmed total yields of compound III from compound I superimposable on those obtained by synthesis Scheme 1, confirming the validity thereof as alternatives for obtaining compound III.
Compound III was subsequently reacted, in solution with a proton acceptor, with an alkylsulphonyl chloride under stirring at room temperature for a period ranging from 1 to 2 hours to give compound IV (X=R5SO3; wherein R5 is methyl, ethyl or p-tolyl) with yields ranging from 88 to 95%.
Suitable proton acceptors are represented by pyridine, triethylamine, lutidine, preferably pyridine. Alkylsulphonyl chlorides that may be used are represented by, but not limited to, methanesulphonyl chloride, ethanesulphonyl chloride or p-toluenesulphonyl chloride, preferably methanesulphonyl chloride.
Compound IVa is then treated with from 4 to 8 equivalents of sodium alkyl mercaptide (compound of the general formula R4SNa; wherein R4 is. independently, a linear, branched or cyclic, saturated or unsaturated C1-8 alkyl residue) in dimethylformamide with agitation at from 90 to 100xc2x0 C. for a period ranging from 2 to 5 hours to give compound V with yields ranging from 90 to 95% and an HPLC titre of 97%.
If the R4 group of the allyl mercaptide is an alkyl radical larger than methyl or ethyl, compound IVa (X=R5SO3; wherein R5 is methyl, ethyl or p-tolyl) can be converted beforehand into a halogenated derivative IVb (preferably X=I) in order to facilitate nucleophilic substitution. That last step is carried out in acetone solution with agitation at reflux temperature in the presence of lithium iodide to give compound IVb in quantitative yields.
Compound V is converted into the final compound VI by treating a heterogeneous mixture of compound V in an aprotic solvent with a reducing agent at a temperature ranging from 20 to 45xc2x0 C. for from 2 to 6 hours. Reducing agents that may be used in that step are lithium aluminium hydride or sodium dihydrido-bis(2-methoxyethoxy)aluminate; the preferred reducing agent is sodium 7dihydridro-bis(2-methoxyethoxy)aluminate. Aprotic solvents that may be used in that step are tetrahydrofuran, dioxane and toluene; the preferred solvent is toluene. The yields of that step are from 80 to 99%.
The physico-chemical characteristics of the product VI obtained (R4=CH3) are in good agreement with the data reported in literature for this product; the HPLC purity is 96%.
The high degree of purity of the pergolide base obtained (HPLC titre of 96% on the crude reaction material), the high global yields of the process (66%) starting from D-8-methoxycarbonylergoline and the ready availability of the primary starting material make this process competitive compared with those known from the prior art.
Several salts of compound VI (Pergolide) may be prepared, including acid addiction salts of inorganic acids as well as salts derived from non toxic organic salts. The preparation of the above salts, and particularly the methanesulfonate (mesylate), may be easily realised following known literature procedures, as for example U.S. Pat. No. 4,166,182 and EP-0003667, herein incorporated as references.